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    Clinical Trial Results:
    Sclero XIII: A phase II ,double-blind, randomized, placebo-controlled study to investigate pharmacokinetics (PK), safety and efficacy of intravenous factor XIII treatment in patients with systemic sclerosis

    Summary
    EudraCT number
    2014-001101-40
    Trial protocol
    GB  
    Global end of trial date
    06 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Dec 2019
    First version publication date
    19 Dec 2019
    Other versions
    Summary report(s)
    Sclero XIII study report

    Trial information

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    Trial identification
    Sponsor protocol code
    13/0417
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02551042
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IRAS: 150751
    Sponsors
    Sponsor organisation name
    University College London, Joint Research Office
    Sponsor organisation address
    149 Tottenham Court Road, London, United Kingdom,
    Public contact
    Prof Christopher Denton, University College London, +44 02073177544, c.denton@ucl.ac.uk
    Scientific contact
    Prof Christopher Denton, University College London, +44 02073177544, c.denton@ucl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1.To identify any effects of factor XIII treatment on clinical manifestations of Sleroderma (SSc) 2.To investigate factor XIII safety 3.To measure individual factor XIII levels in patients with SSc 4.To measure the effects of factor XIII treatment on factor XIII PK parameters. 5.To explore effects of factor XIII on thrombospondin expression
    Protection of trial subjects
    The study involved an initial PK open label arm to assess the safety and tolerability of the IMP in the patient population as well as generating a dosing algorithm that would be used in the double blind, randomized placebo-controlled treatment arm. This was built into the study in order to to minimize safety issues .
    Background therapy
    Immunosuppressants such as mycophenolate, cyclophosphamide, and methotrexate are prescribed to manage disease symptoms as there is currently no approved medication.
    Evidence for comparator
    This is a phase II, double-blind, randomised, placebo-controlled study to investigate the pharmacokinetics, safety and efficacy of intravenous factor XIII treatment in patients with systemic sclerosis, as there is no approved drug for Diffuse Systemic Sclerosis (DcSSC) a placebo arm is the relevant comparator
    Actual start date of recruitment
    09 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 26
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment window was 24/11/2015 to 22/01/2018

    Pre-assignment
    Screening details
    PK arm- 8 participants were screened and randomized Treatment arm- 22 participants were screened and 18 randomized. There were 4 screen failures and 1 withdrawal

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Both the investigators and subject were blinded to treatment group allocation. Only the pharmacy staff and designated unblinded nurse were unblinded in order for them to review study participants Factor XIII levels.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Active treatment
    Arm description
    6 participants with diffuse and 6 with limited SSc were randomly allocated to receive active treatment;
    Arm type
    Experimental

    Investigational medicinal product name
    Fibrogammin®P, coagulation factor XIII concentrate (Human)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Individual dosing to 220% of normal every 14 days for 24 weeks. FXIII levels to be measured before and after injection

    Arm title
    Placebo
    Arm description
    3 participants with diffuse SSc and 3 with limited SSc were randomly allocated to receive placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Sodium Chloride, 0,9%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Standardised placebo administration every 14 days for 24 weeks total

    Arm title
    PK arm
    Arm description
    4 patients with limited and 4 patients with diffuse systemic sclerosis received a single dose of factor XIII and levels were monitored over a six-week period
    Arm type
    PK safety

    Investigational medicinal product name
    Fibrogammin®P, coagulation factor XIII concentrate (Human)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants will receive a single intravenous injection of factor XIII concentrate either 20 or 40 IU/kg, depending on starting levels. Participants with starting levels great than or equal to 90% of normal will receive 20 IU/kg. Participants with starting levels less than 90% of normal will receive 40 IU/kg

    Number of subjects in period 1
    Active treatment Placebo PK arm
    Started
    12
    6
    8
    Completed
    11
    6
    8
    Not completed
    1
    0
    0
         poor vascular access
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    26 26
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    19 19
        From 65-84 years
    7 7
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    0 ± 0 -
    Gender categorical
    Units: Subjects
        Female
    25 25
        Male
    1 1
    Subject analysis sets

    Subject analysis set title
    PK
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    (PK) phase of the trial aimed to assess the safety and tolerability of the IMP in the SSc patient. It also aimed to generate data to produce a dosing algorithm that could be used in the Treatment Phase.

    Subject analysis set title
    Active Treatment
    Subject analysis set type
    Per protocol
    Subject analysis set description
    12 patients on active treatment, 6 with limited disease and 6 with diffuse disease

    Subject analysis set title
    Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    6 participants on Placebo, 3 with limited disease and 3 diffuse

    Subject analysis sets values
    PK Active Treatment Placebo
    Number of subjects
    8
    12
    6
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    6
    13
        From 65-84 years
    2
    5
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59 ±
    59.8 ±
    57.5 ±
    Gender categorical
    Units: Subjects
        Female
    7
    12
    6
        Male
    1
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Active treatment
    Reporting group description
    6 participants with diffuse and 6 with limited SSc were randomly allocated to receive active treatment;

    Reporting group title
    Placebo
    Reporting group description
    3 participants with diffuse SSc and 3 with limited SSc were randomly allocated to receive placebo.

    Reporting group title
    PK arm
    Reporting group description
    4 patients with limited and 4 patients with diffuse systemic sclerosis received a single dose of factor XIII and levels were monitored over a six-week period

    Subject analysis set title
    PK
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    (PK) phase of the trial aimed to assess the safety and tolerability of the IMP in the SSc patient. It also aimed to generate data to produce a dosing algorithm that could be used in the Treatment Phase.

    Subject analysis set title
    Active Treatment
    Subject analysis set type
    Per protocol
    Subject analysis set description
    12 patients on active treatment, 6 with limited disease and 6 with diffuse disease

    Subject analysis set title
    Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    6 participants on Placebo, 3 with limited disease and 3 diffuse

    Primary: Skin involvement

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    End point title
    Skin involvement
    End point description
    Skin involvement measured with modified Rodnan skin score
    End point type
    Primary
    End point timeframe
    Baseline to 24 weeks
    End point values
    Active Treatment Placebo
    Number of subjects analysed
    12
    6
    Units: whole numbers
    12
    6
    Attachments
    Untitled (Filename: Capture.PNG)
    Statistical analysis title
    Skin Involvement
    Comparison groups
    Placebo v Active Treatment
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    ≤ 0.05
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
    Notes
    [1] - Please see attached chart

    Primary: Raynaud condition score

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    End point title
    Raynaud condition score
    End point description
    Raynaud condition score
    End point type
    Primary
    End point timeframe
    Baseline to week 24
    End point values
    Active Treatment Placebo
    Number of subjects analysed
    12
    6
    Units: whole numbers
    12
    6
    Attachments
    Untitled (Filename: Capture.PNG)
    Statistical analysis title
    Raynauds condition score
    Comparison groups
    Active Treatment v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    ≤ 0.05
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval

    Secondary: Pulmonary function

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    End point title
    Pulmonary function [2]
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 24
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pulmonary function not assessed in the PK arm, see attached report for full information.
    End point values
    Active treatment Placebo Active Treatment Placebo
    Number of subjects analysed
    12
    6
    12
    6
    Units: whole numbers
    12
    6
    12
    6
    Attachments
    Secondary endpoints
    Statistical analysis title
    Pulmonary function
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    ≤ 0.05
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
    Notes
    [3] - Descriptive analysis

    Secondary: Hand function measured with Cochin hand function

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    End point title
    Hand function measured with Cochin hand function
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks
    End point values
    Active Treatment Placebo
    Number of subjects analysed
    Units: whole numbers
    12
    6
    Attachments
    Untitled (Filename: Secondary endpoints.PNG)
    No statistical analyses for this end point

    Secondary: • Quality of life measured with SF36 quality of life questionnaire

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    End point title
    • Quality of life measured with SF36 quality of life questionnaire
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks
    End point values
    Active Treatment Placebo
    Number of subjects analysed
    Units: whole numbers
    12
    6
    Attachments
    Untitled (Filename: Secondary endpoints.PNG)
    No statistical analyses for this end point

    Secondary: Prevention of new DU (Digital Ulcers)

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    End point title
    Prevention of new DU (Digital Ulcers)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks
    End point values
    Active Treatment Placebo
    Number of subjects analysed
    Units: whole numbers
    12
    6
    Attachments
    Untitled (Filename: Secondary endpoints.PNG)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to end of study
    Adverse event reporting additional description
    Safety and tolerability of Factor XIII assessed by physical examination (including digital ulcer characterization),Vital signs (heart rate, blood pressure, pulse, body weight) and Clinical laboratory parameters. Study doctor also enquired about adverse events at every study visit between baseline and end of study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Active Treatment
    Reporting group description
    -

    Reporting group title
    PK arm
    Reporting group description
    -

    Serious adverse events
    Placebo Active Treatment PK arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Active Treatment PK arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    12 / 12 (100.00%)
    0 / 8 (0.00%)
    General disorders and administration site conditions
    Diarrhea, DU, Dizziness
         subjects affected / exposed
    5 / 6 (83.33%)
    12 / 12 (100.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2016
    Main updates to Protocol detailed below: -Addition of routine blood tests -Clarification in urine pregnancy tests "to women of childbearing potential" -Clarification to avoid unnecessary capillaroscopy testing. -Patients will be monitored for a minimum of one house after dosing. -Updates to Concomitant medications to ensure patient safety i.e use of Bosentan included as an exclusion criteria - Dosing algorithm for treatment phase explained in detail -Update to dose modifications

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    As this was a small trial, all analysis is descriptive and no robust conclusion about efficacy can be drawn from the data. therefore this study confirms feasibility of recruitment to the designed trial and provides a platform for future studies.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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